Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

Karen J. Woodward, Julie Stampalia, Hannah Vanyai, Hashika Rijhumal, Kim Potts, Fiona Taylor, Joanne Peverall, Tanya Grumball, Soruba Sivamoorthy, Hamid Alinejad-Rokny, John Wray, Andrew Whitehouse, Lakshmi Nagarajan, Jacqueline Scurlock, Sabine Afchani, Matthew Edwards, Ashleigh Murch, John Beilby, Gareth Baynam, Cathy Kiraly-Borri & 2 others Fiona McKenzie, Julian I. T. Heng

Research output: Contribution to journalArticle

Abstract

Background Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. Methods We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. Results We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. Conclusion Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.

Original languageEnglish
Article number507
Number of pages17
JournalMolecular genetics & genomic medicine
Volume7
Issue number2
DOIs
Publication statusPublished - Feb 2019

Cite this

Woodward, Karen J. ; Stampalia, Julie ; Vanyai, Hannah ; Rijhumal, Hashika ; Potts, Kim ; Taylor, Fiona ; Peverall, Joanne ; Grumball, Tanya ; Sivamoorthy, Soruba ; Alinejad-Rokny, Hamid ; Wray, John ; Whitehouse, Andrew ; Nagarajan, Lakshmi ; Scurlock, Jacqueline ; Afchani, Sabine ; Edwards, Matthew ; Murch, Ashleigh ; Beilby, John ; Baynam, Gareth ; Kiraly-Borri, Cathy ; McKenzie, Fiona ; Heng, Julian I. T. / Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance. In: Molecular genetics & genomic medicine. 2019 ; Vol. 7, No. 2.
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title = "Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance",
abstract = "Background Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. Methods We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. Results We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. Conclusion Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.",
keywords = "22q11.2, atypical, autism spectrum disorder, central 22q11.2, duplication, LCR22B to LCR22D, LOW-COPY REPEATS, MICRODUPLICATION 22Q11.2, DELETION, TBX1, MALFORMATIONS, EXPRESSION, DEFECTS, MEDIATE, GENE",
author = "Woodward, {Karen J.} and Julie Stampalia and Hannah Vanyai and Hashika Rijhumal and Kim Potts and Fiona Taylor and Joanne Peverall and Tanya Grumball and Soruba Sivamoorthy and Hamid Alinejad-Rokny and John Wray and Andrew Whitehouse and Lakshmi Nagarajan and Jacqueline Scurlock and Sabine Afchani and Matthew Edwards and Ashleigh Murch and John Beilby and Gareth Baynam and Cathy Kiraly-Borri and Fiona McKenzie and Heng, {Julian I. T.}",
year = "2019",
month = "2",
doi = "10.1002/mgg3.507",
language = "English",
volume = "7",
journal = "Molecular Genetics and Genomic Medicine",
issn = "2324-9269",
publisher = "John Wiley & Sons",
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Woodward, KJ, Stampalia, J, Vanyai, H, Rijhumal, H, Potts, K, Taylor, F, Peverall, J, Grumball, T, Sivamoorthy, S, Alinejad-Rokny, H, Wray, J, Whitehouse, A, Nagarajan, L, Scurlock, J, Afchani, S, Edwards, M, Murch, A, Beilby, J, Baynam, G, Kiraly-Borri, C, McKenzie, F & Heng, JIT 2019, 'Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance' Molecular genetics & genomic medicine, vol. 7, no. 2, 507. https://doi.org/10.1002/mgg3.507

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance. / Woodward, Karen J.; Stampalia, Julie; Vanyai, Hannah; Rijhumal, Hashika; Potts, Kim; Taylor, Fiona; Peverall, Joanne; Grumball, Tanya; Sivamoorthy, Soruba; Alinejad-Rokny, Hamid; Wray, John; Whitehouse, Andrew; Nagarajan, Lakshmi; Scurlock, Jacqueline; Afchani, Sabine; Edwards, Matthew; Murch, Ashleigh; Beilby, John; Baynam, Gareth; Kiraly-Borri, Cathy; McKenzie, Fiona; Heng, Julian I. T.

In: Molecular genetics & genomic medicine, Vol. 7, No. 2, 507, 02.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

AU - Woodward, Karen J.

AU - Stampalia, Julie

AU - Vanyai, Hannah

AU - Rijhumal, Hashika

AU - Potts, Kim

AU - Taylor, Fiona

AU - Peverall, Joanne

AU - Grumball, Tanya

AU - Sivamoorthy, Soruba

AU - Alinejad-Rokny, Hamid

AU - Wray, John

AU - Whitehouse, Andrew

AU - Nagarajan, Lakshmi

AU - Scurlock, Jacqueline

AU - Afchani, Sabine

AU - Edwards, Matthew

AU - Murch, Ashleigh

AU - Beilby, John

AU - Baynam, Gareth

AU - Kiraly-Borri, Cathy

AU - McKenzie, Fiona

AU - Heng, Julian I. T.

PY - 2019/2

Y1 - 2019/2

N2 - Background Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. Methods We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. Results We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. Conclusion Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.

AB - Background Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. Methods We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. Results We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. Conclusion Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.

KW - 22q11.2

KW - atypical

KW - autism spectrum disorder

KW - central 22q11.2

KW - duplication

KW - LCR22B to LCR22D

KW - LOW-COPY REPEATS

KW - MICRODUPLICATION 22Q11.2

KW - DELETION

KW - TBX1

KW - MALFORMATIONS

KW - EXPRESSION

KW - DEFECTS

KW - MEDIATE

KW - GENE

U2 - 10.1002/mgg3.507

DO - 10.1002/mgg3.507

M3 - Article

VL - 7

JO - Molecular Genetics and Genomic Medicine

JF - Molecular Genetics and Genomic Medicine

SN - 2324-9269

IS - 2

M1 - 507

ER -